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PD-153035

PD153035 is a ATP-competitive EGFR inhibitor with an IC50 and Ki of 25 and 6 pM. PD153035 effectively blocks the enhancement of mitogenesis, induction of early gene expression, and oncogenic transformation that occur in response to EGF receptor stimulation. With human fibroblasts and epidermoid carcinoma cells, PD153035 at nanomolar concentrations rapidly inhibits EGFR autophosphorylation. With breast and ovarian cancer cells, PD153035 not only blocks cell growth via inhibition of EGFR, but also upregulates the expression of the tumor suppressor retinoic acid receptor-beta 2 (RAR-beta2).

Current developer:   PFizer. 

PD153035 is a potent (Ki = 6 pm) and specific inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase that suppresses tyrosine phosphorylation of the EGF receptor in A431 cells at nanomolar concns. in cell culture. Kunkel etal had performed research on the pharmacokinetics of this compd. and its ability to rapidly suppress phosphorylation of the EGF receptor in A431 human epidermoid tumors grown as xenografts in immunodeficient nude mice. Following a single i.p. dose of 80 mg/kg, the drug levels in the plasma and tumor rose to 50 and 22 .mu.M within 15 min. While the plasma levels of PD153035 fell below 1 .mu.M by 3 h, in the tumors, it remained at micromolar concns. for at least 12 h. The tyrosine phosphorylation of the EGF receptor was rapidly suppressed by 80-90% in the tumors. However, receptor phosphorylation returned to control levels after 3 h despite the continued presence of the drug at concns. which, based on previous in vitro results, were predicted to maintain inhibition. EGF-stimulated tyrosine kinase activity in tumor exts. was decreased and recovered in parallel with the effects of PD153035 on receptor phosphorylation; although, the activity had reached only about half of the control activity after three hours. These results demonstrate the potential for using small mol. inhibitors to inhibit the EGF receptor tyrosine kinase in vivo; although, a fair evaluation of their potential anti-cancer activity will have to wait for solns. to problems with sustained delivery, which may allow us to maintain suppression of EGF receptor phosphorylation. See Kunkel, Mark W.; Hook, Kenneth E.; Howard, Curtis T.; Przybranowski, Sally; Roberts, Billy J.; Elliott, William L.; Leopold, Wilbur R. .Inhibition of the epidermal growth factor receptor tyrosine kinase by PD 153035 in human A431 tumors in athymic nude mice.   Investigational New Drugs (1996), Volume Date 1995-1996, 13(4), 295-302.

 1: Meng X, Loo BW Jr, Ma L, Murphy JD, Sun X, Yu J. Molecular imaging with 11C-PD153035 PET/CT predicts survival in non-small cell lung cancer treated with EGFR-TKI: a pilot study. J Nucl Med. 2011 Oct;52(10):1573-9. Epub 2011 Sep 8. PubMed PMID: 21903741.

2: Cheng CM, Lee YJ, Wang WT, Hsu CT, Tsai JS, Wu CM, Ou KL, Yang TS. Determining the binding mode and binding affinity constant of tyrosine kinase inhibitor PD153035 to DNA using optical tweezers. Biochem Biophys Res Commun. 2011 Jan 7;404(1):297-301. Epub 2010 Dec 2. PubMed PMID: 21130075.

3: Cavalheiro RA, Marin RM, Rocco SA, Cerqueira FM, da Silva CC, Rittner R, Kowaltowski AJ, Vercesi AE, Franchini KG, Castilho RF. Potent cardioprotective effect of the 4-anilinoquinazoline derivative PD153035: involvement of mitochondrial K(ATP) channel activation. PLoS One. 2010 May 17;5(5):e10666. PubMed PMID: 20498724; PubMed Central PMCID: PMC2871796.

4: Prada PO, Ropelle ER, Mourão RH, de Souza CT, Pauli JR, Cintra DE, Schenka A, Rocco SA, Rittner R, Franchini KG, Vassallo J, Velloso LA, Carvalheira JB, Saad MJ. EGFR tyrosine kinase inhibitor (PD153035) improves glucose tolerance and insulin action in high-fat diet-fed mice. Diabetes. 2009 Dec;58(12):2910-9. Epub 2009 Aug 20. PubMed PMID: 19696185; PubMed Central PMCID: PMC2780887.

5: Liu N, Li M, Li X, Meng X, Yang G, Zhao S, Yang Y, Ma L, Fu Z, Yu J. PET-based biodistribution and radiation dosimetry of epidermal growth factor receptor-selective tracer 11C-PD153035 in humans. J Nucl Med. 2009 Feb;50(2):303-8. Epub 2009 Jan 21. PubMed PMID: 19164239.

6: Wang H, Yu JM, Yang GR, Song XR, Sun XR, Zhao SQ, Wang XW, Zhao W. Further characterization of the epidermal growth factor receptor ligand 11C-PD153035. Chin Med J (Engl). 2007 Jun 5;120(11):960-4. PubMed PMID: 17624262.

7: Grunt TW, Tomek K, Wagner R, Puckmair K, Zielinski CC. The DNA-binding epidermal growth factor-receptor inhibitor PD153035 and other DNA-intercalating cytotoxic drugs reactivate the expression of the retinoic acid receptor-beta tumor-suppressor gene in breast cancer cells. Differentiation. 2007 Nov;75(9):883-90. Epub 2007 Jul 2. PubMed PMID: 17608728.

8: Grunt TW, Tomek K, Wagner R, Puckmair K, Kainz B, Rünzler D, Gaiger A, Köhler G, Zielinski CC. Upregulation of retinoic acid receptor-beta by the epidermal growth factor-receptor inhibitor PD153035 is not mediated by blockade of ErbB pathways. J Cell Physiol. 2007 Jun;211(3):803-15. PubMed PMID: 17286282.

9: Samén E, Thorell JO, Fredriksson A, Stone-Elander S. The tyrosine kinase inhibitor PD153035: implication of labeling position on radiometabolites formed in vitro. Nucl Med Biol. 2006 Nov;33(8):1005-11. PubMed PMID: 17127174.

10: Jia C, Zhou Z, Liu R, Chen S, Xia R. EGF receptor clustering is induced by a 0.4 mT power frequency magnetic field and blocked by the EGF receptor tyrosine kinase inhibitor PD153035. Bioelectromagnetics. 2007 Apr;28(3):197-207. PubMed PMID: 17019730.

11: Cole GW Jr, Alleva AM, Reddy RM, Maxhimer JB, Zuo J, Schrump DS, Nguyen DM. The selective epidermal growth factor receptor tyrosine kinase inhibitor PD153035 suppresses expression of prometastasis phenotypes in malignant pleural mesothelioma cells in vitro. J Thorac Cardiovasc Surg. 2005 May;129(5):1010-7. PubMed PMID: 15867774.

12: Rocco SA, Velho JA, Marin RM, de Arruda Rolim Filho L, Vercesi AE, Rittner R, Franchini KG. High performance liquid chromatography analysis of a 4-anilinoquinazoline derivative (PD153035), a specific inhibitor of the epidermal growth factor receptor tyrosine kinase, in rat plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Mar 25;817(2):297-302. PubMed PMID: 15686998.

13: He XY, Huang JA, Xie W, Jiang LY, Wang YD. [Role of PD153035 in the induction of apoptosis of XG-1 myeloma cell line]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2004 Oct;26(5):492-5. Chinese. PubMed PMID: 15562758.

14: Goossens JF, Bouey-Bencteux E, Houssin R, Hénichart JP, Colson P, Houssier C, Laine W, Baldeyrou B, Bailly C. DNA interaction of the tyrosine protein kinase inhibitor PD153035 and its N-methyl analogue. Biochemistry. 2001 Apr 17;40(15):4663-71. PubMed PMID: 11294633.

15: Egeblad M, Mortensen OH, van Kempen LC, Jäättelä M. BIBX1382BS, but not AG1478 or PD153035, inhibits the ErbB kinases at different concentrations in intact cells. Biochem Biophys Res Commun. 2001 Feb 16;281(1):25-31. PubMed PMID: 11178955.

16: Fredriksson A, Johnström P, Thorell JO, von Heijne G, Hassan M, Eksborg S, Kogner P, Borgström P, Ingvar M, Stone-Elander S. In vivo evaluation of the biodistribution of 11C-labeled PD153035 in rats without and with neuroblastoma implants. Life Sci. 1999;65(2):165-74. PubMed PMID: 10416822.

17: Bos M, Mendelsohn J, Kim YM, Albanell J, Fry DW, Baselga J. PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner. Clin Cancer Res. 1997 Nov;3(11):2099-106. PubMed PMID: 9815602.

18: Kunkel MW, Hook KE, Howard CT, Przybranowski S, Roberts BJ, Elliott WL, Leopold WR. Inhibition of the epidermal growth factor receptor tyrosine kinase by PD153035 in human A431 tumors in athymic nude mice. Invest New Drugs. 1996;13(4):295-302. PubMed PMID: 8824347.